This invention relates to anti-inflammatory imidazoles.
Lombardino, in U.S. Pat. No. 3,707,475 discloses anti-inflammatory 4,5-diaryl-2-substituted imidazoles.
Doebel, in U.S. Pat. Nos. 3,505,350 and 3,651,080, respectively, discloses anti-inflammatory 4-alkyl-5-aryl-1-substituted-2-mercapto imidazoles and 4-alkyl-2-alkylthio-5-aryl-1-substituted imidazoles.
Zauer, K., et al., in Chem. Ber. 106, 1638 (1973), disclose 4,5-bis(4-methoxyphenyl)-2-methylthioimidazole and 4,5-bis(4-chlorophenyl)-2-methylthioimidazole but do not suggest any use.
A number of references, such as Current Sci. India 17, 184-85 (1948) and Acta. Chem. Acad. Sci. Hung. 79 (2) 197-212 (1973) disclose 2-(substituted-thio)-4,5-diphenyl imidazoles and 1-methyl-2-(substituted thio)-4,5-diphenyl imidazoles with substituents such as methyl, propyl, allyl, and acetonyl.
There is a continuing need for safe and effective anti-inflammatory agents. Inflammation is a disease process characterized by redness, fever, swelling, and pain. Arthritis, in its various forms, is the most prevalent, chronic, and severe of the inflammatory diseases. Traumatic injury and infection also involve inflammation, and anti-inflammatory drugs are often used in their treatment. The usefulness of most commercial anti-inflammatories is limited because of toxicity and adverse side-effects. Many produce gastric irritation and other effects, such as changes in blood cells and central nervous system. Adreno-cortical steroids produce gastric irritation and suppression of normal adrenal function.
The Journal of the America Medical Association, Vol. 224, No. 5 (Supplement), 1973 "Primer on the Rheumatic Diseases" states that "Immunologic reactions appear to play a major role in the perpetuation of rheumatoid inflammation." Widely used non-steroidal anti-inflammatory drugs, such as aspirin, indomethacin, phenylbutazone and ibuprofen have no effect on these immunologic reactions, but merely relieve the symptoms of the inflammatory response; these drugs do not stop the progressive and ultimately destructive processes of rheumatoid arthritis. Immunosuppressive drugs, such as cyclophosphamide, are effective in the treatment of rheumatoid arthritis, but are too toxic for wide-spread use.
The present invention results from efforts to develop new anti-arthritic compounds with good anti-inflammatory and immunoregulatory activity and minimal side effects that could be more effective in treating arthritis than presently available drugs.
Compounds of this invention have demonstrated unique properties in several tests of anti-inflammatory and immunoregulatory activity. The biological profiles of these compounds are different from non-steroidal anti-inflammatory drugs and immunosuppressive drugs. These unique properties provide for a novel approach to the treatment of rheumatoid arthritis, and may also be useful in the treatment of other diseases involving altered immune states.
In addition to anti-inflammatory and immunoregulating properties, compounds of this invention have demonstrated analgesic activity in a test procedure. This additional property is desirable in treatment of arthritis or related diseases; however, such compounds can be employed solely to alleviate pain.